software

serverssearch tool

versioning

programming

XML

RDFOWL

data sets

semantic web

PubChem

screening

fluorescence

small molecule

biological assay

novel chemical tools

chemical probes

high-thoughput screening (HTS)

ChemBank

PDSP

pharmaceutical

chemical biology

cheminformatics

biological pathways

disease networks

structural biology

biomedical knowledge

technology end point

ATP Luciferin Coupled

activityviability

Beta-Lactamase Induction

binding based

calcium redistribution

caspase activity

dehydrogenase activity

cyclic AMP redistribution

energy transfer

enzyme reporter

enzyme substrate based

Fluorogenic substrateGFP induction

standards

controlled vocabulary

indexing

subject indexing schemes

authorized terms

taxonomies

thesauri

subject headings

natural language

library

tags homographs

synonyms

polysemes

conceptsstructure

searchknowledge

specificity

article

meta-data

information exchange

classification

nomenclaturesemantic

domain

propertiesannotation

object

classes

individuals

BioAssay Ontology (BAO)

Stephan Schürer, PhD

ICBO, Buffalo, July 30 2011

sschurer@med.miami.edu

One of the most important approaches to find novel entry points for drug discovery programs

Historically in pharmaceutical companies Since ~2005, massive NIH effort (MLI) to make HTS

accessible to public sector research PubChem is the major repository of HTS data More recently: EU-OpenScreen project

Background for BioAssay Ontology

High-throughput screening

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Lack of standardized assay annotations No standardized endpoint names or formats

Data is rarely re-used(!)Common queries cannot be askedAnalysis across different data sets is difficultIntegration with other databases is difficult

No knowledge model for assays and screening results

Motivation for BioAssay Ontology

Large public screening data setsPubChem, ChEMBL, PDSP, ChemBank, Binding DB

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• Identify inhibitors of kinases in biochemical assays.• Identify compounds active in multiple luciferase reporter

gene assays.• Identify compounds active in cell viability assays and

organize by cell lines and assay types.• Identify active compounds in assays related to pathway X.• …

Queries the Ontology should be able to answer

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Leverage the aggregated corpus of publically available HTS data to infer molecular mechanism of actions (MMOA) of small molecule perturbagens in biological model systems.

Schürer et al. “BioAssay Ontology Annotations Facilitate Cross-Analysis of Diverse High-throughput Screening Data Sets” J Biomol Screen 2011 (16), 415-426.

BAOSearch Software (beta):http://baosearch.ccs.miami.edu Query, explore, download BAO-annotated PubChem content Some semantic search capabilities

Project Website and Wiki with relevant materials and documentation:http://www.bioassayontology.org/http://www.bioassayontology.org/wiki

BAO Products and Resources

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Application / user focus vs. “universal” ontologies Efficiency vs. “realism” of representations Rapid application development

Orthogonal ontologies vs. Ontology mapping Universal “realism” vs. domain or application-specific

Chemical bond: 2D structure graph, 3D rule based, molecular mechanics, semi-empirical, up-initio QM

Disease Virtual world

Questions / Discussion points

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Collaborative ontology development Collaborative vs. individual effort Control over development and focus / application focus Rapid application development Quality

Aligning BAO to upper level ontology (BFO) Benefits vs. required resources Do upper level ontologies matter for specialized

applications?

Questions / Discussion points

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Aligning BAO with OBI Some level of overlap OBI: process-oriented (model the investigation) BAO: purpose of categorization and analysis of HTS data BAO model becomes more complex if based on OBI

How do we do it practically Define missing assays to OBI and MIREOT back? Quick term templates (QTT)? Define our relations as short-cut relationships (using RO)?

Questions / Discussion points

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Additional slides

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BAO-facilitated Example for Analysis(Luciferase Assays)

Details in: Schürer et al. “BioAssay Ontology Annotations Facilitate Cross-Analysis of Diverse High-throughput Screening Data Sets” J Biomol Screen 2011 (16), 415-426.

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Panel AssaySingle ConcOtherConc-responseA

ssay

Cou

nt

Most promiscuous reporter gene compounds

Most promiscuous reporter gene compoundsRep

orte

r DR

Repor

ter S

CVi

abilit

y DR

Viab

ility S

CEn

z Acti

v DR

Enz A

ctiv S

CAT

P DR

ATP

SCLu

cifer

in DR

Lucif

erin

SC

Promiscuity Index0 10.2

Com

poun

ds

Luciferase Enzyme Inhibitors

Generally cytotoxic

Examples: Cytotoxic Series

Cluster Reporter PCIdx: 0.56Cluster Reporter Active: 58Cluster Viability PCIdx: 0.64Cluster Viability Active 27 Cluster Reporter PCIdx: 0.48

Cluster Reporter Active: 23Cluster Viability PCIdx: 0.45Cluster Viability Active 10

Cluster Reporter PCIdx: 0.41Cluster Reporter Active: 29Cluster Viability PCIdx: 0.57Cluster Viability Active 13

Daunorubicin

Emetine

Examples: Luciferase Inhibitor Series

Cluster Size: 6Cluster Reporter PCIdx: 0.61Cluster Reporter Active: 101Cluster EnzActivity PCIdx: 0.58Cluster EnzActivity: 15

Cluster Size: 4Cluster Reporter PCIdx: 0.38Cluster Reporter Active: 52Cluster EnzActivity PCIdx: 0.61Cluster EnzActivity: 11

Cluster Size: 5Cluster Reporter PCIdx: 0.46Cluster Reporter Active: 77Cluster EnzActivity PCIdx: 0.58Cluster EnzActivity: 14

Schürer et al. “BioAssay Ontology Annotations Facilitate Cross-Analysis of Diverse High-throughput Screening Data Sets” J Biomol Screen 2011 (16), 415-426.

1) Development of the Bioassay Ontology

2) Annotation of assays and assay results(content curation)

3) Development of software tools

BAO Project: Three major components

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BAO design to describe assays

Application of BAO: BAO Search Software

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http://baosearch.ccs.miami.edu/baosearch/

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BAO: Concept Search

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Biochemical Assays with IC50 < 1 mM

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Chemical structure search

BioAssay Ontology (NCBO bioportal and project site):http://bioportal.bioontology.org/ontologies/45410http://www.bioassayontology.org/visualize/

Terminology / annotations for biochemical assays: http://www.bioassayontology.org/>Assay Annotation Template

Over 1000 BAO-annotated assays from PubChem (available in BAOSearch)

BAO Products and Resources

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• Chris Mader• Amar Koleti• Nakul Datar• Sreeharsha

Venkatapuram• Felimon Gayanilo

• Mark Southern

• Saminda Abeyruwan• Uma Vempati• Magdalena Przydzial• Kunie Sakurai• Robin Smith• Yuanyuan Jia• Caty Chung

• Ubbo Visser• Vance Lemmon• Mitsunori Ogihara

• Nick Tsinoremas

http://bioassayontology.org

sschurer@med.miami.edu

Acknowledgements

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